Molecular Bumpers and Glues: Rewiring Cell Signaling for Smarter Medicines
New research led by the University of Minnesota Medical School demonstrates that molecules acting as “molecular bumpers” and “molecular glues” can rewire G protein-coupled receptor (GPCR) signaling, turning the cell’s busiest receptors into precision tools-opening the door to a new generation of safer, smarter medicines. The findings were published today in Nature.
About one-third of all drugs approved by the Food and Drug Management target the GPCR family. Although they are the largest family of successful drug targets, scientists recognize that these receptors still hold untapped potential as targets for new treatments. These receptors can activate a plethora of signaling pathways downstream of 16 different G proteins, resulting in different cellular and physiological effects. Some of these pathways may be therapeutically useful, while others lead to unwanted side effects, limiting the potential for therapeutic progress.
“The capability to design drugs that produce only selected signaling outcomes may yield safer,more effective medicines. Until now, it hasn’t been obvious how to do this,” said Lauren Slosky, Ph.D., an assistant professor at the University of Minnesota Medical School, and the senior and corresponding author of the study.
In this study, the research team, including chemists at the Sanford Burnham prebys Medical Revelation Institute (SBP), describe a strategy to
Allosteric Modulators Offer Precision Targeting of GPCRs
G protein-coupled receptors (GPCRs) are crucial drug targets, but achieving selectivity between subtypes remains a significant challenge. Researchers, led by Madelyn N. Moore, have designed allosteric modulators that dramatically shift GPCR G protein subtype selectivity. This breakthrough, published in Nature, offers a new approach to drug development with potentially fewer side effects.
GPCRs don’t just bind to orthosteric ligands – the typical drug-binding sites.They also have allosteric sites. These sites, when bound by allosteric modulators, can subtly alter the receptor’s shape and function. The team focused on engineering these modulators to influence which G protein a GPCR activates. This is key because different G proteins trigger different cellular responses.
The researchers used a combination of structural biology,computational modeling,and medicinal chemistry to design allosteric modulators for the muscarinic acetylcholine receptor M2 (M2R). They successfully created compounds that could switch the M2R’s preference from activating Gq proteins to activating Gi/o proteins. This shift is significant because Gq activation typically leads to increased cellular excitability, while Gi/o activation generally has the opposite effect.
Conventional drug discovery often struggles with subtype selectivity. Drugs frequently bind to multiple GPCR subtypes, causing unwanted side effects. Allosteric modulators offer a potential solution. by targeting a site distinct from the orthosteric binding pocket, they can fine-tune receptor behavior without fully blocking the natural ligand’s access. This allows for a more nuanced pharmacological effect.
The study demonstrates the power of rational drug design. The team didn’t just stumble upon these modulators; they engineered them based on a deep understanding of the receptor’s structure and function. This approach could be applied to other GPCRs, opening up new avenues for treating a wide range of diseases.
This research represents a major step forward in GPCR drug discovery. It highlights the potential of allosteric modulation to achieve precise control over receptor signaling and minimize off-target effects.
Source: Madelyn N. Moore et al, Designing allosteric modulators to change GPCR G protein subtype selectivity, Nature (2025). DOI: 10.1038/s41586-025-09643-2